Post-marketing safety concerns with palbociclib: a disproportionality analysis of the FDA adverse event reporting system.

OBJECTIVES: To explore the association between palbociclib and related adverse events (AEs) in the real world through U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: The signal strength of palbociclib-related AEs was done by disproportionality analysis. Clinical priority of palbociclib-related AEs was scored and ranked by assessing five different features. Outcome analysis, time to onset analysis, dose-report /AEs number analysis, and stratification analysis were all performed. RESULTS: There were 61,821 'primary suspected (PS)' reports of palbociclib and 195,616 AEs associated with palbociclib. The four algorithms simultaneously detected 18 positive signals at the SOC level, and 65 positive signals at the PT level. Bone marrow failure, neuropathy, peripheral, pleural effusion, myelosuppression, pulmonary edema, and pulmonary thrombosis were also found to have positive signals. Gender (female vs male, χ2 = 5.287, p = 0.022) and age showed significant differences in serious and non-serious reports. Palbociclib-related AEs had a median onset time of 79 days (interquartile range [IQR] 20-264 days). CONCLUSIONS: The study identified potential Palbociclib-related AEs and offered warnings for special AEs, providing further data for palbociclib safety studies in breast cancer patients. Nonetheless, prospective clinical trials are needed to validate these results and explain their relationship.

Effect of ertugliflozin on renal function and cardiovascular outcomes in patients with type 2 diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: The global prevalence of type 2 diabetes mellitus (T2DM) is growing yearly. The efficacy of ertugliflozin (ERT), a recently licensed anti-diabetic drug, has been widely reported. However, additional evidence-based data is required to ensure its safety. In particular, convincing evidence on the effects of ERT on renal function and cardiovascular outcomes is needed. METHODS: We searched PubMed, Cochrane Library, Embase, and Web of Science for randomized placebo-controlled trials of ERT for T2DM published up to August 11, 2022. Cardiovascular events here mainly refer to acute myocardial infarction and angina pectoris (AP) (including stable AP and unstable AP). The estimated glomerular filtration rate (eGFR) was used to measure renal function. The pooled results are risk ratios (RRs) and 95% confidence intervals (CIs). Two participants worked independently to extract data. RESULTS: We searched 1516 documents and filtered the titles, abstracts, and full text, 45 papers were left. Seven trials met the inclusion criteria and were ultimately included in the meta-analysis. The meta-analysis found that ERT reduced eGFR by 0.60 mL·min-1·1.733 m-2 (95% CI: -1.02--0.17, P = .006) in patients with T2DM when used for no more than 52 weeks and these differences were statistically significant. Compared with placebo, ERT did not increase the risk of acute myocardial infarction (RR 1.00, 95% CI: 0.83-1.20, P = .333) and AP (RR 0.85, 95% CI: 0.69-1.05, P = .497). However, the fact that these differences were not statistically significant. CONCLUSION: This meta-analysis shows that ERT reduces eGFR over time in people with T2DM but is safe in the incidence of specific cardiovascular events.

Effect of potassium-competitive acid blockers on human gut microbiota: a systematic review and meta-analysis.

Background: Vonoprazan has been reported to exert more potent and long-lasting gastric acid inhibition than proton pump inhibitors, potentially leading to a greater impact on the gut microbiota. This study aimed to clarify changes in microbial diversity and bacterial composition after VPZ treatments. Methods: We searched from PubMed, Embase, WOS, Scopus, Cochrane Library, and ClinicalTrials.gov (all years up to May 2023). The primary outcomes were alpha and beta diversity, as well as differences in gut microbiota composition between before and after VPZ treatments. We performed a meta-analysis to uncover the potential changes in human gut microbiota among VPZ users by pooled mean difference (MD) with a 95% confidence interval (CI). The risk of bias was assessed using the ROBINS-I tool. Results: A total of 12 studies were included to compare differences before and after VPZ treatments. Compared with baseline, alpha diversity was significantly reduced after VPZ treatments and gradually returned to baseline with longer follow-up. At the phylum level, there was a decrease in the relative abundance of Firmicutes and Actinobacteria, while Bacteroidetes increased compared with baseline. At the genus level, we found a significant decrease in the relative abundance of Coprococcus and Bifidobacterium and a significant increase in the relative abundance of Bacteroides compared with those before treatment. In subgroup analyses according to country and participants, we found differences in microbial changes after VPZ treatments. Conclusion: Vonoprazan can affect the changes of gut microbiota, which may be potentially associated with its strong ability of acid inhibition. However, due to the large heterogeneity, further studies are required to validate these findings. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023412265.

Impact of Antimicrobial Stewardship Programs on Antibiotic Use and Drug Resistance: Analysis of Data from Maternal and Child Health Care Hospitals in Hubei Province, China.

OBJECTIVE: To evaluate the impact of Antimicrobial Stewardship Programs (ASPs) on antibiotic use and drug resistance. METHODS: This was a retrospective, multicenter, management intervention study. The data from 85 maternity hospitals (maternal and child health care hospitals) in Hubei province from 2012 to 2019 were collected. The indicators related to antimicrobial drug use included the utilization rate of different grades of antimicrobial drugs, the intensity of antimicrobial agent use, the rational use of prophylactic antimicrobial agents before class I surgical incision, and pathogenic detection and consultation rates before antimicrobial drug use. RESULTS: Since the implementation, the purchase of antimicrobial agents in hospitals has been maintained within the prescribed range, and the defined daily dose system (DDDs) of antimicrobial agents has been reduced, prophylactic use and accurate treatment of antimicrobial agents related to class I surgical incision have been more reasonable. With the implementation of ASPs, the detection rate of imipenem-resistant Acinetobacter baumannii, cefotaxime-resistant Escherichia coli, and methicillin-resistant Staphylococcus aureus has been decreased in China from national bacterial resistance surveillance data. CONCLUSION: ASPs have positive effects on antibiotic use and drug resistance in 85 maternity hospitals (maternal and child health care hospitals).

Ophiopogon Saponin C1 Inhibits Lung Tumors by Stabilizing Endothelium Permeability via Inhibition of PKCδ.

As the most frequent cause of cancer-related death worldwide, lung cancer is closely related to inflammation. The interaction between tumor cells and inflammatory cells promotes tumor development and metastasis. During tumor development, vascular endothelial cells form the most important barrier to prevent tumor cell migration to the blood and tissue. Increased vascular permeability provides favorable conditions for the migration of tumor cells, and endothelial tight junctions are an important component of the vascular barrier. Protein kinase C δ is involved in the occurrence of non-small cell lung cancer and regulates vascular permeability and tight junction protein expression. Src kinase was reported to play an important role in TNF-α-induced endothelial inflammation. Ophiopogon Saponin C1 is a new chemical compound isolated from Liriope muscari, but its pharmacological activities have not been fully elucidated. Therefore, we tested the protective effects of C1 on endothelial permeability in a model of TNF-α-induced endothelial inflammation by transendothelial electrical resistance and sodium fluorescein assays and verified these results in a nude mouse model of experimental pulmonary adenocarcinoma metastasis. We further elucidated the mechanism of C1, which was based on the PKCδ and Src proteins, by Western blotting. C1 can inhibit lung cancer in vivo, regulate the level of plasma inflammation in tumor-bearing mice, and protect the pulmonary vascular barrier against injury induced by cancer. It was investigated the expression and distribution of the TJ index protein ZO-1 in mouse vascular endothelium and HUVECs and found that C1 could inhibit the degradation and breakage of the ZO-1 protein. Related signaling experiments confirmed that C1 can inhibit TNF-α and activation of PKCδ and Src kinase. This study laid the foundation for further analysis of new drugs with clear mechanisms and independent intellectual property rights of traditional Chinese medicines.

Advances in the antitumor activities and mechanisms of action of steroidal saponins.

The steroidal saponins are one of the saponin types that exist in an unbound state and have various pharmacological activities, such as anticancer, anti-inflammatory, antiviral, antibacterial and nerves-calming properties. Cancer is a growing health problem worldwide. Significant progress has been made to understand the antitumor effects of steroidal saponins in recent years. According to reported findings, steroidal saponins exert various antitumor activities, such as inhibiting proliferation, inducing apoptosis and autophagy, and regulating the tumor microenvironment, through multiple related signaling pathways. This article focuses on the advances in domestic and foreign studies on the antitumor activity and mechanism of actions of steroidal saponins in the last five years to provide a scientific basis and research ideas for further development and clinical application of steroidal saponins.

DT-13 Ameliorates TNF-α-Induced Vascular Endothelial Hyperpermeability via Non-Muscle Myosin IIA and the Src/PI3K/Akt Signaling Pathway.

DT-13(25(R,S)-ruscogenin-1-O-[ß-d-glucopyranosyl-(1→2)][ß-d-xylopyranosyl-(1→3)]-ß-d-fucopyranoside) has been identified as an important factor in TNF-α-induced vascular inflammation. However, the effect of DT-13 on TNF-α-induced endothelial permeability and the potential molecular mechanisms remain unclear. Hence, this study was undertaken to elucidate the protective effect of DT-13 on TNF-α-induced endothelial permeability and the underlying mechanisms in vivo and in vitro. The in vivo results showed that DT-13 could ameliorate endothelial permeability in mustard oil-induced plasma leakage in the skin and modulate ZO-1 organization. In addition, the in vitro results showed that pretreatment with DT-13 could increase the transendothelial electrical resistance value and decrease the sodium fluorescein permeability coefficient. Moreover, DT-13 altered the mRNA and protein levels of ZO-1 as determined by real-time PCR, Western blotting, and immunofluorescence analyses. DT-13 treatment decreased the phosphorylations of Src, PI3K, and Akt in TNF-α-treated human umbilical vein endothelial cells (HUVECs). Further analyses with PP2 (10 µM, inhibitor of Src) indicated that DT-13 modulated endothelial permeability in TNF-α-induced HUVECs in an Src-dependent manner. LY294002 (10 µM, PI3K inhibitor) also had the same effect on DT-13 but did not affect phosphorylation of Src. Following decreased expression of non-muscle myosin IIA (NMIIA), the effect of DT-13 on the phosphorylations of Src, PI3K, and Akt was abolished. This study provides pharmacological evidence showing that DT-13 significantly ameliorated the TNF-α-induced vascular endothelial hyperpermeability through modulation of the Src/PI3K/Akt pathway and NMIIA, which play an important role in this process.

Allergens in red ginseng extract induce the release of mediators associated with anaphylactoid reactions.

BACKGROUND: Anaphylactoid reactions induced by preparations containing red ginseng have been reported. The aim of this study is to evaluate the allergenicity and screen potential allergens in red ginseng extract thoroughly. METHODS: Red ginseng extract (RGE) and different fractions of RGE were prepared and evaluated by measuring the degranulation and viability of rat basophilic leukemia 2H3 (RBL-2H3) cells. Potential allergens were screened by RBL-2H3 cell extraction and allergenicity verified in RBL-2H3 cells, mouse peritoneal mast cells, Laboratory of Allergic Disease 2 (LAD2) human mast cells and mice, respectively. RESULTS: 80% ethanol extract of red ginseng extract induced mast cell degranulation with less cytotoxicity, but 40% ethanol extract could not. Ginsenoside Rd and 20(S)-Rg3 could induce a significant increase in ß-hexosaminidase release, histamine release and translocation of phosphatidylserine in RBL-2H3 cells. Ginsenoside Rd and 20(S)-Rg3 also increased ß-hexosaminidase release and the intracellular Ca2+ concentration in mouse peritoneal mast cells and LAD2 cells. In addition, histamine levels in serum of mice were elevated dose-dependently. CONCLUSIONS: Ginsenoside Rd and 20(S)-Rg3 are potential allergens that induce the release of mediators associated with anaphylactoid reactions. Our study could guide optimization of methods associated with Rd/20(S)-Rg3-containing preparations and establishment of quality standards for safe application of Traditional Chinese Medicines.

The Myosin II Inhibitor, Blebbistatin, Ameliorates FeCl3-induced Arterial Thrombosis via the GSK3ß-NF-κB Pathway.

Arterial thrombosis and its related diseases are major healthcare problems worldwide. Blebbistatin is an inhibitor of myosin II, which plays an important role in thrombosis. The aim of our study is to explore the effect and potential mechanism of blebbistatin on arterial thrombosis. A ferric chloride (FeCl3) solution at a concentration of 5% was used to induce carotid artery thrombosis in mice. Immunohistochemistry and immunofluorescence staining were used to detect the expression or activation of non-muscle myosin heavy chain IIA (NMMHC IIA), tissue factor (TF), GSK3ß and NF-κB. Blebbistatin (1 mg/kg, i.p.) significantly reduced carotid artery thrombosis induced by FeCl3 solution in mice, inhibited NMMHC IIA expression and impeded TF expression via the GSK3ß-NF-κB signalling pathway in mouse arterial vascular tissues. The present study demonstrates that blebbistatin may impede TF expression partly via the Akt/GSK3ß-NF-κB signalling pathways in the endothelium in a FeCl3 model, shedding new insights into the pathogenesis of arterial thrombosis and providing new clues for the development of antithrombotic drugs.

Microbial hydroxylation and glycosylation of pentacyclic triterpenes as inhibitors on tissue factor procoagulant activity.

To discover new inhibitors on tissue factor procoagulant activity, 20 pentacyclic triterpenes were semi-synthetized through microbial transformation and assayed on the model of human THP-1 cells stimulated by lipopolysaccharide. In the biotransformation two types of reactions were observed, regio-selective hydroxylation and glycosylation. The bioassay results showed that most of tested compounds were significant effective on this model and two of the biotransformation products 23-hydroxy-28-O-ß-d-glucopyranosyl betulinic acid (3d) and 28-O-ß-d-glucopyranosyl oleanic acid (1a) exhibited most potential activities with the IC50 values of 0.028, 0.035nM respectively. The preliminary structure and activity relationship analysis revealed that the aglycones with single free hydroxyl group on the skeleton (1, 1j) were less effective than that with more free hydroxyl groups (1d, 1f, 2), mono-glycosylation can significantly enhance their inhibitory effects. Our findings also provide some potential leading compounds for tissue factor-related diseases, such as cancer and cardiovascular diseases.

YiQiFuMai Powder Injection Protects against Ischemic Stroke via Inhibiting Neuronal Apoptosis and PKCδ/Drp1-Mediated Excessive Mitochondrial Fission.

YiQiFuMai (YQFM) powder injection has been reported to be used in cardiovascular and nervous system diseases with marked efficacy. However, as a treatment against diseases characterized by hypoxia, lassitude, and asthenia, the effects and underlying mechanisms of YQFM in neuronal mitochondrial function and dynamics have not been fully elucidated. Here, we demonstrated that YQFM inhibited mitochondrial apoptosis and activation of dynamin-related protein 1 (Drp1) in cerebral ischemia-injured rats, producing a significant improvement in cerebral infarction and neurological score. YQFM also attenuated oxidative stress-induced mitochondrial dysfunction and apoptosis through increasing ATP level and mitochondria membrane potential (Δψm), inhibiting ROS production, and regulating Bcl-2 family protein levels in primary cultured neurons. Moreover, YQFM inhibited excessive mitochondrial fission, Drp1 phosphorylation, and translocation from cytoplasm to mitochondria induced by oxidative stress. We provided the first evidence that YQFM inhibited the activation, association, and translocation of PKCδ and Drp1 upon oxidative stress. Taken together, we demonstrate that YQFM ameliorates ischemic stroke-induced neuronal apoptosis through inhibiting mitochondrial dysfunction and PKCδ/Drp1-mediated excessive mitochondrial fission. These findings not only put new insights into the unique neuroprotective properties of YQFM associated with the regulation of mitochondrial function but also expand our understanding of the underlying mechanisms of ischemic stroke.